Introduction

Atopic dermatitis (AD) is one of the most common chronic inflammatory dermatoses, occurring often in families with atopic predisposition and other atopic diseases (1). Pruritus and eczematous lesions are important clinical manifestations of AD, with pruritus being the most debilitating symptom of the disease (2-4). The distribution and morphology of the lesions vary with age, and especially during infancy sensitive skin areas, such as the face, neck, and scalp, are affected (1, 5). Although the pathophysiology of AD is not completely understood, accumulating evidence suggests a complex interplay between genetic, immunological, and environmental factors contributing to impaired epidermal barrier function and allergic inflammation (1, 5-8). The worldwide prevalence of AD ranges between 10 and 20% in the pediatric population, depending on the geographic region (9, 10). Among patients with AD, the majority have an onset in infancy, with about 73% presenting symptoms before the age of 2 years, underscoring the importance of early effective and safe management in the infant age group (7, 11, 12). Furthermore, persistence of AD is prolonged with age of onset, as patients who were diagnosed between the ages of 0 to 1 year or between the ages of 6 to 11 years had a median persistence of AD of 3 or 12.5 years, respectively (13). Currently, AD cannot be cured and management focuses on restoring the disturbed epidermal barrier function and tempering the inflammatory skin responses, to ultimately treat and reduce the risk of flares on the long-term (14). The recently published consensus-based European guidelines for treatment of AD, recommend topical corticosteroids (TCS) as first-line anti-inflammatory therapy in infants with mild-to-moderate AD (14). However, TCS are associated with several limitations due to potential local side effects, including skin infections, impairment of the epidermal barrier function, and skin atrophy, which limit their use for treatment of sensitive skin areas (14, 15). Additionally, percutaneous absorption of TCS through the disrupted skin may lead to systemic exposure and subsequent growth impairment (15). As a result of these safety limitations, adherence to TCS is often poor due to corticophobia (14, 16). The topical calcineurin inhibitors (TCIs) – pimecrolimus 1% cream (Elidel®, Meda, Stockholm, Sweden) and tacrolimus 0.03% and 0.1% ointment (Protopic®, Astellas, Tokyo, Japan) – are another class of anti-inflammatory drugs, which are indicated for mild-to-moderate and moderate-to-severe AD, respectively (17-20). TCIs have a more selective mechanism of action compared to TCS and do not cause impairment of the epidermal barrier function and skin atrophy (14, 21, 22). Therefore, the European guidelines for treatment of AD recommend TCIs for use in sensitive skin areas as well as for long-term treatment (14). Evidence from clinical trials on the use of TCIs for the treatment of AD in infants mostly exists for pimecrolimus. Based on this evidence, pimecrolimus is approved in infants aged ≥3 months in 10 countries (Elidel® [pimecrolimus] cream 1%, Prescribing Information [Australia, Brazil, Canada, India, Indonesia, Israel, New Zealand, Philippines, Russia, and Thailand]). However, pimecrolimus is currently not approved in Europe and the United States (US) in children below the age of 2 years due to initial safety concerns. In 2006, the Food & Drug Administration (FDA) added a black-box warning to the TCIs labels to emphasize that long-term use has not been established, warning about a theoretical increased risk of lymphoma and skin malignancies, and indicating that use of TCIs in infants is not approved (17). In the same year, the European Medicines Agency (EMA) limited the use of TCIs to second-line treatment of AD following a safety review (18). During the last 20 years, both the short- and long-term safety of pimecrolimus for the treatment of AD in infants has been extensively evaluated. Furthermore, a previous recommendation from an international group of dermatologists already concluded in 2015 that use of pimecrolimus should no longer be restricted to children above the age of 2 years (23). This review aims to provide the rationale behind the high need to initiate treatment of AD during infancy and to update the previous consensus guidance on the use of pimecrolimus in infants between 3 months and 2 years of age.